Compositions and methods for enhancing corticosteroid delivery

ABSTRACT

The present invention comprises a composition, method of enhancing potency and method of delivering corticosteroids in a vehicle comprising at least two penetration enhancers, and solvents and emulsifiers. The propylene glycol and penetration enhancers are present in ratio to the total of the propylene glycol, penetration enhancers, and solvents and emulsifiers of at least about 0.70.

RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 10/037,360, filed Dec.21, 2001 now U.S. Pat. No. 6,765,001

FIELD OF THE INVENTION

Topical corticosteroids are useful for their anti-inflammatory,anti-pruritic and vasoconstrictive actions. Corticosteroids (orcorticoids) are any steroids (lipids that contain a hydrogenatedcyclopentoperhydrophenanthrene ring system) elaborated by the adrenalcortex (except sex hormones of adrenal origin) in response to therelease of adrenocorticotrophin or adrenocorticotropic hormone by thepituitary gland, or to any synthetic equivalent, or to angiotensin II.Corticosteroids include but are not limited to alclometasonedipropionate, amcinonide, amcinafel, amcinafide, beclamethasone,betamethasone, betamethasone dipropionate, betamethasone valerate,clobetasone propionate, chloroprednisone, clocortelone, cortisol,cortisone, cortodoxone, difluorosone diacetate, descinolone, desonide,defluprednate, dihydroxycortisone, desoximetasone, dexamethasone,deflazacort, diflorasone diacetate, dichlorisone, esters ofbetamethasone, flucetonide, flucloronide, fluorocortisone, flumethasone,flunisolide, fluocinonide, fluocinolone acetonide, flucortolone,fluperolone, fluprednisolone, fluroandrenolone acetonide, fluocinoloneacetonide, flurandrenolide, fluorametholone, fluticasone propionate,hydrocortisone, hydrocortisone butyrate, hydrocortisone valerate,hydrocortamate, medrysone, meprednisone, methylprednisone,methylprednisolone, mometasone furoate, paramethasone, prednisone,prednisolone, prednidone, triamcinolone acetonide, and triamcinolone.

Hydrocortisone was the first corticosteroid found to be topicallyeffective. Other more potent glueoeorticoids, which are a subset ofcorticosteroids that affect carbohydrate metabolism, inhibitcorticotropin secretion, and possess pronounced anti-inflammatoryactivity, have since been developed. Currently, topical steroids areamong the most frequently prescribed of all dermatological drugproducts.

It is believed that glucocorticoids exert their potent anti-inflammatoryeffects by inhibiting the formation of prostaglandins and otherderivatives of the arachidonic acid pathway. It is known thatglucocorticoids inhibit the release of phospholipase A2, the enzymeresponsible for liberating arachidonic acid from cell membranes, thusinhibiting the arachidonic acid pathway. Currently, it is believed thatglucocorticoids inhibit phospholipase A2, in cells by directly inducingphosphorylation of the enzyme.

Steroids are commonly divided into two classes, fluorinated andnonfluorinated. Fluorinated steroids have been chemically modified toincrease potency. These modifications, such as halogenation andmethylation, can result in improved activity within the target cell andin decreased breakdown to inactive metabolites. These modifications canalso lead to more systemic side effects. However, modification of thechemical structure of the steroid is not the only way to increasepotency.

The potency of topical steroid preparations is strongly correlated totheir absorption through the skin. Treatment of the skin prior toapplication of the topical steroid may also affect the absorption of thecompounds into the skin. Treatments with keratolytics or with fatsolvents (such as acetone) disrupt the epidermal barrier and increasepenetration. Hydrating the skin has also been shown to increase thepenetration of the corticosteroids.

Once absorbed through the skin, topical corticosteroids are handledthrough pharmacokinetic pathways similar to systemically administeredcorticosteroids. The potencies of corticosteroids vary greatly and it isa challenge to increase the potency of any particular steroid.

BACKGROUND OF THE INVENTION

The clinical effectiveness of corticoids is related to four basicproperties: vasoconstriction, antiproliferative effects,immunosuppression, and anti-inflammatory effects. Topical steroids causethe capillaries in the superficial dermis to constrict, thus reducingerythema. The ability of a given glucocorticoid agent to causevasoconstriction usually correlates with its anti-inflammatory potency.Vasoconstrictor assays are used in the art and by the U.S. Food and DrugAdministration for determining the potency of topical corticosteroidpreparations. Topical glucocorticoid preparations have been divided inthe field into seven classes based on potency based on double-blindclinical studies and vasoconstrictor assays. Class 1 includes the mostpotent, while class 7 contains the least potent.

The following glucocorticoid preparations were designated inFitzpatrick, Dermatology in General Medicine, 5^(th) edition, CD-ROM,1999, Table 243-1, with the following classes.

TABLE 1 Corticosteroid Preparation Corticosteroid Class SourceTemovate ® Clobetasone 1 Glaxo Wellcome Cream 0.05% propionateTemovate ® Clobetasone 1 Glaxo Wellcome ointment 0.05% propionateDiprolene ® Betamethasone 1 Schering Corp. cream 0.05% dipropionateDiprolene ® Betamethasone 1 Schering Corp. ointment 0.05% dipropionatePsorcon ® Diflorasone 1 Dermik Laboratories, ointment diacetate Inc.Cyclocort ® Amcinonide 2 Fujisawa ointment 0.1% Diprolene ®Betamethasone 2 Schering Corp. cream AF dipropionate 0.05% Diprosone ®Betamethasone 2 Schering Corp. ointment 0.05% dipropionate Elocon ®Mometasone 2 Schering Corp. ointment 0.1% furoate Florone ® Diflorasone2 Dermik ointment 0.05% diacetate Halog ® cream Halcinonide 2Westwood-Squibb 0.1% Lidex ® gel Fluocinonide 2 Medicis Pharmaceuticals0.05% Corp. Lidex ® cream Fluocinonide 2 Medicis Pharmaceuticals 0.05%Corp. Lidex ® Fluocinonide 2 Medicis Pharmaceuticals ointment 0.05%Corp. Maxiflor ® Diflorasone 2 Allergan Herbert ointment 0.05% diacetateTopicort ® Desoximetasone 2 Medicis Pharmaceuticals cream 0.25% Corp.Topicort ® gel Desoximetasone 2 Medicis Pharmaceuticals 0.05% Corp.Topicort ® Desoximetasone 2 Medicis Pharmaceuticals ointment 0.25% Corp.Aristocort A ® Triamcinolone 3 Fujisawa ointment 0.1% acetonideCutivate ® Fluticasone 3 Glaxo Wellcome ointment propionate 0.005%Cyclocort ® Amcinonide 3 Fujisawa cream 0.1% Cyclocort ® Amcinonide 3Fujisawa Lotion 0.1% Diprosone ® Betamethasone 3 Schering Corp. cream0.05% dipropionate Florone ® cream Diflorasone 3 Dermik 0.05% diacetateHalog ® Halcinonide 3 Westwood-Squibb ointment 0.1% Lidex ® EFluocinonide 3 Medicis Pharmaceutical cream 0.05% Corp. Maxiflor ®Diflorasone 3 Allergan Herbert cream 0.05% diacetate Valisone ®Betamethasone 3 Schering Corp. ointment 0.1% valerate Cordran ®Flurandrenolide 4 Oclassen ointment 0.05% Elocon ® cream Mometasone 4Schering Corp. 0.1% furoate Kenalog ® Triameinolone 4 Westwood-Squibbcream 0.1% acetonide Synalar ® Fluocinolone 4 Medicis Pharmaceuticalsointment acetonide Corp. 0.025% Westcort ® Hydrocortisone 4Westwood-Squibb ointment 0.2% valerate Cordran ® Flurandrenolide 5Oclassen cream 0.05% Cutivate ® Fluticasone 5 Glaxo Wellcome cream 0.05%propionate Diprosone ® Betamethasone 5 Schering Corp. lotion 0.05%dipropionate Kenalog ® Triamcinolone 5 Westwood-Squibb lotion 0.1%acetonide Locoid ® cream Hydrocortisone 5 Ferndale 0.1% butyrateSynalar ® cream Flucinolone 5 Medicis Pharmaceuticals 0.025% acetonideCorp. Valisone ® Betamethasone 5 Schering Corp. cream 0.1% valerateWestcort ® Hydrocortisone 5 Westwood-Squibb cream 0.2% valerateAclovate ® Alclometasone 6 Glaxo Wellcome cream 0.05% dipropionateAclovate ® Alclometasone 6 Glaxo Wellcome ointment 0.05% dipropionateAristocort ® Triamcinolone 6 Fujisawa cream 0.1% acetonide Desowen ®Desonide 6 Galderma cream 0.05% Synalar ® Fluocinolone 6 MedicisPharmaceuticals solution 0.01% acetonide Corp. Synalar ® creamFluocinolone 6 Medicis Pharmaceuticals 0.01% acetonide Corp.Tridesilon ® Desonide 6 Miles cream 0.05% Valisone ® Betamethasone 6Schering Corp. lotion 0.1% valerate Topicals with 7 hydrocortisonedexamethasone, flumethasone, prednisolone, and methylprednisolone

All percentages given are weight percentages unless otherwise noted.

Although there is no significant difference between potencies withinClass 2, within Class 1 Temovate® cream or ointment is significantlymore potent than Class 1 Diprolone® cream or ointment of Schering andClass 1 Psorcon® ointment of Dermik Laboratories, Inc.

Several factors such as the vehicle, the integrity of the epidermalbarrier, and the use of occlusive dressings affect the percutaneousabsorption and resulting potency of corticosteroids regardless of theintrinsic potency of the glucocorticosteroid (or glucocorticoid)molecule. Further, inflammation and/or other disease processes in theskin increase percutaneous absorption.

The vehicle in which the corticoid is incorporated may be as importantas the corticoid molecule itself in determining the potency of a givenformulation because the vehicle affects the amount of corticoid that isreleased in any given period of time, and its absorption. In manycorticosteroid compositions, the vehicle is as much as 99% of the totalcomposition. Very occlusive vehicles, such as ointments (water-insolublemixtures of oil and petrolatum), increase the corticosteroid effectbecause they provide increased hydration of the stratum corneum andincrease the skin's permeability. By covering the skin with an occlusivedressing such as plastic wrap, this effect can be heightened as much as100-fold. The solubility of the corticoid in the vehicle also affectspenetration into the skin.

Creams, which are suspensions of oil in water, have also been used asvehicles for corticosteroids. The compositions of creams vary and arefar less greasy than ointments but do not provide the same degree ofhydration to the skin, and therefore may not have as high penetration asointments. Lotions, which are suspensions of oil in water and aresimilar to creams, are vehicles which include agents to help solubilizethe corticosteroids. Solutions have been used as vehicles and are waterbased with propylene glycol. Gels are solid components at roomtemperature but melt on the skin. Lotions, gels and solutions have lesspenetration than ointments.

Many vehicles for corticosteroids include propylene glycol fordissolving the corticosteroid in the vehicle. In general, compositionsthat contain higher amounts of propylene glycol tend to be more potent.

Vehicles are so important in the potency of corticosteroids thatdifferent formulations containing the same amount of the samecorticosteroid often are in different potency classes. For example,commercially available preparations of 0.05% betamethasone dipropionateare classified as having Class 1, Class 2 or Class 3 potency, dependingon their vehicles (as seen in Table 1).

SUMMARY OF THE INVENTION

The present invention comprises a novel vehicle which is safe fortopical application, stable, and provides increased potency forcorticosteroid preparations, especially fluorinated corticosteroids.

An embodiment of the present invention delivers the corticosteroid in avehicle that comprises a corticosteroid, and (a) at least twopenetration enhancers, including propylene glycol, dimethyl isosorbideor diusopropyl adipate, (b) solvents and/or emulsifiers for thecorticosteroid and optionally the penetration enhancers and (c)optionally, non-solvent/emulsifier ingredients. The vehicle has a ratioof a:(a+b) that is greater than or equal to 0.70, preferably greaterthan or equal to 0.80 and most preferably greater than or equal to 0.90or 0.95.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention enhances the potency of corticosteroidpreparations with a vehicle comprising at least two penetrationenhancers, including diusopropyl adipate, dimethyl isosorbide, propyleneglycol, 1,2,6-hexanetriol, and benzyl alcohol. The corticosteroids withwhich this invention may be used include, but are not limited to,fluorinated corticosteroids.

Another embodiment of the present invention is a method for enhancingthe potency of corticosteroids, preferably fluorinated corticosteroids.The corticosteroid is combined with two or more penetration enhancers(preferably propylene glycol and at least one other penetrationenhancer), and one or more solvents and emulsifiers for thecorticosteroid and optionally penetration enhancers, wherein thepenetration enhancers are present in ratio to the total of thepenetration enhancers, and solvents and emulsifiers of at least about0.70, preferably at least 0.80 and most preferably 0.90 or 0.95.Optionally, one or more inactive ingredients may also be combined withthe corticosteroid.

Another embodiment of the present invention is a method of deliveringcorticosteroids to skin, nails or hair, preferably mammalian skin, mostpreferably human, dog or cat skin. The corticosteroids are preferablyfluorinated corticosteroids. The corticosteroid is combined with two ormore penetration enhancers, and one or more solvents and emulsifiers forthe corticosteroid, wherein the penetration enhancers are present inratio to the total of the penetration enhancers, and solvents andemulsifiers of at least about 0.70, preferably at least 0.85 and mostpreferably 0.90 or 0.95. Optionally, one or more inactive ingredientsmay also be combined with the corticosteroid.

As indicated above, this invention is broadly applicable tocorticosteroids in general, and fluorinated corticosteroids inparticular, most preferably fluocinonide or fluocinolone acetonide. Thefollowing examples show its application to preparations of fluocinonide,a commonly used fluorinated corticosteroid. Fluocinonide is acorticosteroid which is the 21-acetate ester of fluocinolone acetonidewith the chemical namepregna-1,4-diene-3,20-dione,21-(acetyloxy)-6,9-difluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-,(6α,11β, 16α)-.

Compositions containing 0.05% (all percentages are weight percentages)fluocinonide are commonly classified as Class 2.

EXAMPLE 1

Experiments were conducted with embodiments of the present invention andseveral control compositions. Compositions were prepared and theinvestigator was blinded with respect to the compositions. Thirty-sixhealthy volunteers were enrolled for two-day trials. On day 1, a singleapplication of approximately 10 milligrams of at least eightcompositions was made to 1 cm² sites on the lower aspect of eachvolunteer's forearms in accordance with a computer generatedrandomization code. After applying the compositions, the sites wereprotected using a raised perforated guard. The guard was secured to thearm with a non-occlusive tape and the subjects were scheduled to returnthe following day after being instructed to keep the sites dry.

After approximately 16 hours of contact with the skin, the protectiveguards were removed and the compositions were removed from the testsites by gently washing with mild soap and water. Skin vasoconstrictorevaluations were performed on a four point scale (0–3) at approximately18 hours after application.

Scores for skin vasoconstriction were summed for each composition (eachcomposition was applied to thirty-six volunteers and those thirty-sixscores were summed). For each composition tested, the ratio ofpenetration enhancers (a) to the sum of penetration enhancers, andsolvents and emulsifiers (a+b) was calculated (a:(a+b)). All of thecompositions comprise 0.10% fluocinonide.

TABLE 2 Range of 1– 0.94– 0.89– 0.79– 0.69– 0.59– a:(a + b) 0.95 0.900.80 0.70 0.60 0.50 Average of 93 85 71 72 62 58 Summed VasoconstrictorScores *means there were no samples with the range of 0.59 to 0.55.

As seen in the above table, the average vasoconstrictor scores aresignificantly lower for ranges of a:(a+b)<0.70. The corticosteroidpreparations with average vasoconstrictor scores of 58 and 62 aresignificantly less potent than those preparations with averagevasoconstrictor scores of 72 and higher. Scores of 62 and 58 are notsignificantly different. This magnitude of increase in vasoconstrictorscores is typical of an increase in class.

Several control compositions (with 0.10% fluocinonide and no penetrationenhancers, as defined below, were included) were also tested for theirvasoconstrictor scores in the same manner. Therefore, the ratios ofa:(a+b) are zero.

The vasoconstrictor scores are 60.00 and 59.00, which are significantlylower than the present invention's embodiments' vasoconstrictor scores.

Additionally, several other control compositions were tested for theirvasoconstrictor scores (“vasoscores”). These compositions comprised0.10% fluocinonide, and no diisoproyl adipate, propylene glycol ordimethyl isosorbide.

Their vasoscores were 49.00, 47.00 and 44.00.

The experiments also included several Class 1 compositions as comparisonpoints.

Psorcon® ointment by Dermik Laboratories, Inc. of Collegeville, Pa. with0.05% diflorasone diacetate had a vasoscore of 101. Ultravate® ointmentby Westwood-Squibb of Evansville, Ind. with 0.05% halobetasol propionatehad a vasoscore of 97, while Ultravate® cream by Westwood-Squibb with0.05% halobetasol propionate had a vasoscore of 92.

In the ratio of (a): (a+b), penetration enhancers include at least twoof: propylene glycol, diisopropyl adipate, dimethyl isosorbide, 1,2,6hexanetriol, and benzyl alcohol (collectively referred to as “a”). Thesolvents and emulsifiers for the corticosteroid include one or more ofdehydrated alcohol, alcohol (95% v/v) USP, 3-Cyclohexene-1-Methanol,∝4-Dimethyl-a-(4-Methyl-3-Pentenyl)-, Steareth-2, Steareth-21, citricacid, CPE-215, diisopropanolamine (1:9), DIPA/PG (1:9), ethoxydiglycol,Potassium hydroxide (10%), PEG-40 Stearate, PEG-7000, Polysorbate 60,potassium hydroxide (1%), propylene carbonate USP, propylethylene glycol4, oleyl alcohol, sodium lauryl sulfate, sorbitan monostearate, sorbitanstearate, and 1,2,3-Propanetriol Ester (collectively referred to as“b”).

The compositions optionally comprise non-solvent/emulsifier ingredients,such as Glyceryl Stearate (and) PEG-100 Stearate, carbopol 980,cyclomethicone NF, glyceryl monostearate, hydroxyethyl cellulose,hydroxypropyl cellulose, isopropyl myristate, methyl paraben NF, mineraloil, oleic acid NF, PEG-100 Stearate, petrolatum, propyl paraben NF,purified water, stearyl alcohol, white petrolatum, and white wax.

The combination of penetration enhancers used in the invention have aremarkable and unexpected result. Compounds using similar concentrationsof a single penetration enhancer (e.g. propylene glycol as the solepenetration enhancer with 0.10% fluocinonide yielded vasoscores of72.00, and 50.00, depending on the solvents, emulsifiers andnon-solvent/emulsifier ingredients used) do not have similarly high vasoscores. Compositions with the combination of penetration enhancers andformula scores of less than 0.65 also have low vaso scores. Thereforethe invention results in an unexpected increase in potency of thefluocinonide.

EXAMPLE 2

One embodiment of the present invention is detailed in the chart below.

TABLE 3 Component % w/w % w/w Fluocinonide Micronized, 0.1 0.1 USPPropylene Glycol, USP 70.0 74.9 Dimethyl isosorbide 15.0 DiisopropylAdipate 3.0 Isopropyl Myristate, NF 5.0 1,2,6 Trihydroxyhexane 2.5Carbopol 980 1.2 1.0 Diisopropanolamine 85%: 1.2 1.0 propylene glycol(1:9) Citric Acid, USP 0.01 0.01 Purified Water, USP 2.49 2.49 Glycerylmonostearate 2.5 2.5 Glyceryl monostearate & 7.5 7.5 PEG stearate

EXAMPLE 3

Another embodiment of the present invention is detailed in the chartbelow.

TABLE 4 Component % w/w % w/w Fluocinonide Micronized, 0.1 0.1 USPPropylene Glycol, USP 66.8 69.9 Dimethyl isosorbide 5.0 DiisopropylAdipate 2.0 Isopropyl Myristate, NF 5.0 5.0 Carbopol 980 0.5 0.5Diisopropanolamine 85%: 0.5 0.5 propylene glycol (1:9) White Petrolatum,USP 5.0 5.0 Glyceryl monostearate 6.0 6.0 PEG 100 stearate 6.0 6.0Stearyl alcohol, NF 5.0 5.0 Sodium Lauryl Sulfate, NF 0.1

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, that the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are evident from a review of thefollowing claims.

1. A method of delivering corticosteroids to skin comprising: Topicallyapplying a composition comprising one or more corticosteroids with twoor more penetration enhancers, and one or more of the group consistingof solvents and emulsifiers, wherein the penetration enhancers arepresent in ratio to a total of the penetration enhancers, and solventsand emulsifiers of at least about 0.90, and wherein the penetrationenhancers comprise two or more of the group consisting of propyleneglycol, diisopropyl adipate, dimethyl isosorbide, 1,2,6 hexanetriol, andbenzyl alcohol.
 2. A method of delivering corticosteroids to skin,comprising: Topically applying a composition comprising one or morecorticosteroids with two or more penetration enhancers, and one or moreof the group consisting of solvents and emulsifiers, wherein thepenetration enhancers are present in ratio to a total of the penetrationenhancers, and solvents and emulsifiers of at least about 0.90, andwherein the penetration enhancers comprise two or more of the groupconsisting of propylene glycol, diisopropyl adipate and dimethylisosorbide.
 3. A method of delivering corticosteroids to skin,comprising: Topically applying a composition compxisina one or morecorticosteroids with two or more penetration enhancers, and one or moreof the group consisting of solvents and emulsifiers, wherein thepenetration enhancers are present in ratio to a total of the penetrationenhancers, and solvents and emulsifiers of at least about 0.90, andwherein one penetration enhancer comprises propylene glycol.
 4. Themethod of claim 1, wherein the corticosteroid comprises a fluorinatedcorticosteroid.
 5. The method of claim 1, wherein the corticosteroidcomprises fluocinonide.
 6. The method of claim 1, wherein thecorticosteroid comprises fluocinolone acetonide.
 7. The method of claim4, 5, 6, or 1, wherein the corticosteroid is present at about 0.10%. 8.The method of claim 4, 5, 6 or 1, wherein the corticosteroid is presentat at least about 0.50%.
 9. The method of claim 4, 5, 6, or 1, whereinthe corticosteroid is present at at least about 0.25%.
 10. The method ofclaim 1, 2, or 3, wherein the solvents and emulsifiers comprise one ormore of the group consisting of dehydrated alcohol, alcohol (95%v/v)USP, 3-Cyclohexene-1-Methanol, 4-Dimethyl-a-(4-Methyl-3-Pentenyl)-,Steareth-2, Steareth-21, citric acid, CPE-215, diisopropanolamine (1:9),DIPA/PG (1:9), ethoxydiglycol, Potassium hydroxide (10%), PEG-40Stearate, PEG-7000, Polysorbate 60, potassium hydroxide (1%), propylenecarbonate USP, propylethylene glycol 4, oleyl alcohol, sodium laurylsulfate, sorbitan monostearate, sorbitan stearate, and1,2,3-Propanetriyl Ester.
 11. The method of claim 1, 2, or 3, whereinthe composition further comprises one or more non-solvent/emulsifieringredients.
 12. The method of claim 11 wherein thenon-solvent/emulsifier ingredients comprise one or more of the groupconsisting of Glyceryl Stearate (and) PEG-100 Stearate, carbopol 980,cyclomethicone NP, glyceryl monostearate, hydroxyethyl cellulose,hydroxypropyl cellulose, isopropyl myristate, methyl paraben NF, mineraloil, oleic acid NF, PEG-100 Stearate, petrolatum, propyl paraben NF,purified water, stearyl alcohol, white petrolatum, and white wax. 13.The method of claim 1, 2, or 3, wherein the solvents and emulsifiers arepresent at about 4-5%.
 14. The method of claim 12 wherein thenon-solvent/emulsifier ingredients are present at about 11% to about53%.
 15. The method of claim 12 wherein the non-solvent/emulsifieringredients are present at about 11% to about 27%.